At the Cutting Edge
The anti-inflammatory action of glucocorticoids is mediated by cell type specific regulation of apoptosis

https://doi.org/10.1016/S0303-7207(01)00722-5Get rights and content

Abstract

Glucocorticoids play a major role in attenuation of the inflammatory response. These steroid hormones are able to induce apoptosis in cells of the hematopoietic system such as monocytes, macrophages and T-lymphocytes that are involved in the inflammation reaction. In contrast, it was discovered recently that in glandular cells such as the mammary gland epithelia, hepatocytes, ovarian follicular cells and in fibroblasts glucocorticoids protect against apoptotic signals evoked by cytokines, cAMP, tumor suppressors and death genes. The anti-apoptotic effect of glucocorticoids is exerted by modulation of several survival genes such as Bcl-2, Bcl-xL and NFκB, in a cell type-specific manner. Moreover, up regulation or down regulation of the same gene product can occur in a cell type-dependent manner following stimulation by glucocorticoids. This phenomenon is probably due to composite regulatory cross-talk among multiple nuclear coactivators or corepressors, which mediate the transcriptional regulation of the genes, by their interaction with the glucocorticoid receptor (GR). These observations suggest that the anti-inflammatory action of glucocorticoids is exerted by two complementary mechanisms: on the one hand, they induce death of the cells that provoke the inflammation, and on the other hand, they protect the resident cells of the inflamed tissue by arresting apoptotic signals.

Introduction

Glucocorticoids exert a dramatic effect on a variety of mammalian cells. This class of steroid hormones alters both cellular metabolism and gene expression and has long been known to display cytotoxic effects on certain cell types, such as lymphocytes (Munck et al., 1981). Glucocorticoids released from the adrenal gland during periods of stress lead to the catabolism of proteins, lipids, and carbohydrates, and result in an increase in blood sugar (Keller et al., 1983, Homo-Delarche et al., 1991). Glucocorticoids repress or activate gene transcription through interaction with the glucocorticoid receptor (GR) (Cidlowski et al., 1996). The immune system is exquisitely sensitive to the lytic action of glucocorticoids as well as to their metabolic and genetic actions (Cidlowski et al., 1996). Since the complex physiological processes involved in mammalian immune and inflammatory responses are critical for the homeostasis and for the ultimate survival of an organism, their coordinate regulation must assure an appropriate and timely immune reaction without an overreaction that might damage the host (McKay et al., 1999).

It has been known for the last decade that glucocorticoids induce apoptosis in most nucleated cells of the vascular system, such as thymocytes, myeloma cells and peripheral blood monocytes (Table 1; Dowd et al., 1992, Sikora et al., 1996, Chauhan et al., 1997, Schmidt et al., 1999), thus playing a central anti-inflammatory role. Recently, there is increasing evidence for a complementary action of glucocorticoids in protecting the cells, tissues and organs in which the inflammation takes place. This phenomenon raise intriguing questions:

  • 1

    What is the impact of the cell origin (lineage) and final phenotype on the glucocorticoid effect on apoptosis?

  • 2

    Does the anti-apoptotic action of glucocorticoids involve expression or attenuation of the same or different gene products which are involved in their pro-apoptotic action?

  • 3

    Is the anti-apoptotic effect of glucocorticoids mediated by the same receptor as their pro-apoptotic effect?

Section snippets

The glucocorticoid receptor and apoptosis

Most of the effects of glucocorticoids in controlling the apoptotic process in various cell types are believed to be mediated by the GR (Evans-Storms et al., 1995).

Two GR isoforms were characterized recently in human cells, both in health and disease (Cidlowski et al., 1996, Moutsatsou et al., 2000). However, all receptor activity was attributed to the α isoform of GR (GRα). It is not yet clear whether GRβ, which is able to inhibit the activity of GRα, is involved in glucocorticoid induced

Activation of genes involved in apoptosis

Some of the most active genes involved in both induction and prevention of apoptosis, are the members of the Bcl-2 family (Chao et al., 1998, Bergmann et al., 1998). The family consists of proteins which are pro-apoptotic, such as Bcl-xS, Bad, Bax, Bid, and anti-apoptotic, such as Bcl-2, Mcl-1 and Bcl-xL (Nagata, 1997). The various Bcl-2 family members can dimerize with a homologue or heterologue monomer enhancing or antagonizing the function of the other. In this way, the ratio of inhibitors

Mammary gland

Dexamethasone, a stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in the mouse mammary gland (Feng et al., 1995). Injection of Dex led to milk accumulation and was accompanied by an induction of protein kinase A, elevated c-fos, jun B and junD mRNA levels and AP-1 DNA binding activity. Potential target genes of AP-1 such as stromelysin-1, c-jun and SGP-2, which are induced during normal involution, were strongly inhibited in Dex-treated animals.

Anti-apoptotic effect of glucocorticoids: implication in health and disease

Glucocorticoids, among the most widely prescribed compounds in current medical practice, are invaluable in the treatment of inflammatory disorders and pulmonary insufficiency during the prenatal period (Cosmi et al., 1989). These hormones induce apoptosis in lymphocytes and are therefore used as chemotherapeutic agents against many leukemias (Schwartzman et al., 1993, Smets et al., 1999). In contrast, glucocorticoids suppress spontaneous apoptosis of neutrophils, TNFα mediated apoptosis of

Conclusions

The effect of glucocorticoids on apoptosis is dramatically depends on the cell lineage. It seems that cells of hematopoietic origin such as monocytes, macrophages, lymphocytes and lymphoma cells are very sensitive to glucocorticoid stimulation of apoptosis. In contrast, cells of epithelial origin, such as mammary gland, ovarian follicular cells and hepatocytes as well as transformed epithelial cell, such as hepatoma cells and gastric cancer cells are protected by glucocorticoid against various

Acknowledgments

We thank Professors A.M. Kaye and M. Liscovitch for helpful discussion, Dr. K. Tajima for excellent assistance in the graphic work and A.L. Greninger for his assistance in editing and typing the manuscript. The authors work was partially supported by grants from the Yad Abraham Research Center for Cancer Diagnosis and Therapy and Levin Center for Applied Research at the Weizmann Institute of Science, Rehovot, Israel.

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